Blood-brain barrier (BBB) compromise is one of the underlying causes of HIV-1 associated dementia (HAD). Diminished expression of brain microvascular tight junctions (TJ) is observed in brain tissues of HAD patients indicating BBB injury. During the previous period of funding, we established that activation of small dimeric G-proteins (Rho GTPases, such as RhoA) played a central role in alterations of BMVEC TJ. RhoA inhibition prevented migration of HIV-1 infected monocytes, TJ changes and diminished permeability of the BBB. We identified soluble factors that disrupted the barrier and increased monocyte migration across the BBB. We believe that widespread BBB injury seen in areas devoid of leukocyte infiltration could be due to effects of such small molecules produced by activated HIV-1 infected macrophages on the brain side of the barrier. Thus, pro-inflammatory molecules secreted by HIV-1 infected/activated macrophages and interactions between brain endothelial cells and monocytes are two major factors contributing to BBB abnormalities. In addition, our preliminary data indicated that inhibition of glycogen synthase kinase (GSK)-3? prevented activation of Rho GTPases in BMVEC and monocytes, decreased monocyte migration through the BBB and reduced production of inflammatory molecules by activated macrophages, preserving BBB. Recently, GSK-3? inhibitors were recognized as a therapeutic option for HAD treatment due to their direct neuroprotective properties. However, powerful immunomodulatory effects of GSK-3? inhibition have received much less attention in neurodegeneration. GSK-3? suppression as an anti-inflammatory treatment strategy for BBB injury in HAD is the focus of the current proposal. In this competing continuation, we will investigate the therapeutic potential of GSK-3? inhibition and the mechanisms through which it can curtail BBB compromise by addressing the following questions: 1) How GSK-3? inhibition diminishes monocyte migration across the BBB? 2) Can GSK-3? suppression decrease secretion of pro-inflammatory factors in activated HIV-1 infected macrophages attenuating their effects on the BBB? and 3) Can GSK-3? inhibitors prevent BBB dysfunction in an animal model for HIVE via their anti-inflammatory effects? The proposed works will uncover novel mechanisms underlying the immunomodulatory effects of GSK-3? suppression and are highly significant for amelioration of BBB dysfunction in HIV-1 dementia.